Ling W, Lougheed M, Suzuki H, Buchan A, Kodama T, Steinbrecher U P
Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
J Clin Invest. 1997 Jul 15;100(2):244-52. doi: 10.1172/JCI119528.
Oxidized low density lipoprotein (LDL) and acetyl LDL are recognized by the scavenger receptor class A type I/II (SR-AI/II) on macrophages and liver endothelial cells. Several investigators have suggested that there are additional receptors specific for oxidized LDL, but characterization of these alternate receptors for oxidized LDL and evaluation of their quantitative importance in uptake of oxidized LDL has been difficult because of overlapping ligand specificity with SR-AI/II. The purpose of this study was to determine the importance of SR-AI/II in the removal of modified LDL from the bloodstream in vivo. The clearance rate of oxidized LDL from plasma in normal mice was very rapid, and > 90% of injected dose was removed from the blood within 5 min. Clearance rates of oxidized LDL were equally high in SR-AI/II knockout mice, indicating that this receptor is not required for removal of oxidized LDL from plasma. Surprisingly, there was no difference in the clearance rate of acetyl LDL in wild-type and SR-AI/II knockout animals. The plasma clearance of radioiodinated acetyl LDL was almost fully blocked by a 50-fold excess of unlabeled acetyl LDL, but the latter only inhibited oxidized LDL clearance by approximately 5%. Both modified LDLs were cleared mostly by the liver, and there was no difference in the tissue distribution of modified LDL in control and knockout mice. Studies in isolated nonparenchymal liver cells showed that Kupffer cells accounted for most of the uptake of oxidized LDL. Extensively oxidized LDL and LDL modified by exposure to fatty acid peroxidation products were efficient competitors for the uptake of labeled oxidized LDL by SR-AI/II-deficient Kupffer cells, while acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors.
氧化型低密度脂蛋白（LDL）和乙酰化LDL可被巨噬细胞和肝内皮细胞上的I/II型清道夫受体A类（SR-AI/II）识别。几位研究者提出，存在其他对氧化型LDL具有特异性的受体，但由于这些氧化型LDL的替代受体与SR-AI/II的配体特异性重叠，对其进行表征以及评估它们在氧化型LDL摄取中的定量重要性一直很困难。本研究的目的是确定SR-AI/II在体内从血液中清除修饰LDL的重要性。正常小鼠血浆中氧化型LDL的清除率非常快，注射剂量的90%以上在5分钟内从血液中清除。氧化型LDL在SR-AI/II基因敲除小鼠中的清除率同样很高，这表明从血浆中清除氧化型LDL不需要该受体。令人惊讶的是，野生型和SR-AI/II基因敲除动物中乙酰化LDL的清除率没有差异。放射性碘化乙酰化LDL的血浆清除几乎被50倍过量的未标记乙酰化LDL完全阻断，但后者仅抑制氧化型LDL清除约5%。两种修饰的LDL大多由肝脏清除，对照小鼠和基因敲除小鼠中修饰LDL的组织分布没有差异。对分离的非实质肝细胞的研究表明，枯否细胞占氧化型LDL摄取的大部分。广泛氧化的LDL和暴露于脂肪酸过氧化产物修饰的LDL是SR-AI/II缺陷型枯否细胞摄取标记氧化型LDL的有效竞争者，而乙酰化LDL和丙二醛修饰的LDL是相对较差的竞争者。
